Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size
Hackeng, Wenzel M; Brosens, Lodewijk A A; Kim, Joo Young; O'Sullivan, Roderick; Sung, You-Na; Liu, Ta-Chiang; Cao, Dengfeng; Heayn, Michelle; Brosnan-Cashman, Jacqueline; An, Soyeon; Morsink, Folkert H M; Heidsma, Charlotte M; Valk, Gerlof D; Vriens, Menno R; Nieveen van Dijkum, Els; Offerhaus, G Johan A; Dreijerink, Koen M A; Zeh, Herbert; Zureikat, Amer H; Hogg, Melissa; Lee, Kenneth; Geller, David; Marsh, J Wallis; Paniccia, Alessandro; Ongchin, Melanie; Pingpank, James F; Bahary, Nathan; Aijazi, Muaz; Brand, Randall; Chennat, Jennifer; Das, Rohit; Fasanella, Kenneth E; Khalid, Asif; McGrath, Kevin; Sarkaria, Savreet; Singh, Harkirat; Slivka, Adam; Nalesnik, Michael; Han, Xiaoli; Nikiforova, Marina N; Lawlor, Rita Teresa; Mafficini, Andrea; Rusev, Boris; Corbo, Vincenzo; Luchini, Claudio; Bersani, Samantha; Pea, Antonio; Cingarlini, Sara; Landoni, Luca; Salvia, Roberto; Milione, Massimo; Milella, Michele; Scarpa, Aldo; Hong, Seung-Mo; Heaphy, Christopher M; Singhi, Aatur D
(2022) Gut, volume 71, issue 5, pp. 961 - 973
(Article)
Abstract
Objective: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0
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cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. Design: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). Results: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). Conclusions: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
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Keywords: neuroendocrine tumors, pancreatic endocrine tumour, pancreatic islet cell, pancreatic pathology, pancreatic surgery, Gastroenterology, Journal Article
ISSN: 0017-5749
Publisher: BMJ Publishing Group
Note: Publisher Copyright: ©
(Peer reviewed)